JP2019517549A - Ｃ−ｒａｆ阻害薬の治療的使用 - Google Patents
Ｃ−ｒａｆ阻害薬の治療的使用 Download PDFInfo
- Publication number
- JP2019517549A JP2019517549A JP2018564296A JP2018564296A JP2019517549A JP 2019517549 A JP2019517549 A JP 2019517549A JP 2018564296 A JP2018564296 A JP 2018564296A JP 2018564296 A JP2018564296 A JP 2018564296A JP 2019517549 A JP2019517549 A JP 2019517549A
- Authority
- JP
- Japan
- Prior art keywords
- amino acid
- seq
- acid sequence
- chain variable
- variable domain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 68
- 230000001225 therapeutic effect Effects 0.000 title description 21
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 title 1
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 161
- 238000011282 treatment Methods 0.000 claims abstract description 88
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 68
- 102000043136 MAP kinase family Human genes 0.000 claims abstract description 67
- 108091054455 MAP kinase family Proteins 0.000 claims abstract description 67
- 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 claims abstract description 60
- 230000002062 proliferating effect Effects 0.000 claims abstract description 43
- 201000010099 disease Diseases 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 230000034994 death Effects 0.000 claims abstract description 10
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 266
- 229940126062 Compound A Drugs 0.000 claims description 106
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 106
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 98
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 94
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 claims description 89
- 102100030708 GTPase KRas Human genes 0.000 claims description 88
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 claims description 78
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 claims description 78
- 201000001441 melanoma Diseases 0.000 claims description 77
- 102100039788 GTPase NRas Human genes 0.000 claims description 65
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 61
- 230000035772 mutation Effects 0.000 claims description 53
- 239000003814 drug Substances 0.000 claims description 52
- 230000027455 binding Effects 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 46
- 201000011510 cancer Diseases 0.000 claims description 45
- 206010033128 Ovarian cancer Diseases 0.000 claims description 37
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 35
- 208000035475 disorder Diseases 0.000 claims description 33
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 claims description 26
- 238000002648 combination therapy Methods 0.000 claims description 25
- 206010069755 K-ras gene mutation Diseases 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 238000009169 immunotherapy Methods 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 13
- 239000007924 injection Substances 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 10
- 229940122633 C-raf kinase inhibitor Drugs 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 7
- 230000005723 MEK inhibition Effects 0.000 claims description 6
- 230000000750 progressive effect Effects 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229940125374 mitogen-activated extracellular signal-regulated kinase inhibitor Drugs 0.000 claims 5
- 239000006186 oral dosage form Substances 0.000 claims 1
- 238000004806 packaging method and process Methods 0.000 claims 1
- 102000001788 Proto-Oncogene Proteins c-raf Human genes 0.000 abstract description 42
- 230000004075 alteration Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 39
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 38
- 239000003795 chemical substances by application Substances 0.000 description 31
- 230000037361 pathway Effects 0.000 description 31
- 229940124597 therapeutic agent Drugs 0.000 description 31
- 239000000427 antigen Substances 0.000 description 29
- 108091007433 antigens Proteins 0.000 description 29
- 102000036639 antigens Human genes 0.000 description 29
- 230000000694 effects Effects 0.000 description 25
- 108060003951 Immunoglobulin Proteins 0.000 description 23
- 102000018358 immunoglobulin Human genes 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 21
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 21
- 239000012634 fragment Substances 0.000 description 20
- 125000003729 nucleotide group Chemical group 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 18
- 239000002773 nucleotide Substances 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 17
- 108020004707 nucleic acids Proteins 0.000 description 16
- 102000039446 nucleic acids Human genes 0.000 description 16
- 150000007523 nucleic acids Chemical class 0.000 description 16
- 235000018102 proteins Nutrition 0.000 description 16
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 230000006870 function Effects 0.000 description 15
- 210000001744 T-lymphocyte Anatomy 0.000 description 14
- 238000002560 therapeutic procedure Methods 0.000 description 14
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 229940024606 amino acid Drugs 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 13
- 102000048362 human PDCD1 Human genes 0.000 description 13
- 230000028993 immune response Effects 0.000 description 12
- 102100037850 Interferon gamma Human genes 0.000 description 11
- 108010074328 Interferon-gamma Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 230000008901 benefit Effects 0.000 description 11
- 238000001802 infusion Methods 0.000 description 11
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 10
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 102000016914 ras Proteins Human genes 0.000 description 9
- 102220053950 rs121913238 Human genes 0.000 description 9
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 239000012270 PD-1 inhibitor Substances 0.000 description 8
- 239000012668 PD-1-inhibitor Substances 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 238000002512 chemotherapy Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 229940121655 pd-1 inhibitor Drugs 0.000 description 8
- 238000002626 targeted therapy Methods 0.000 description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 238000012492 Biacore method Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 102200006531 rs121913529 Human genes 0.000 description 6
- 102200006538 rs121913530 Human genes 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 101100523539 Mus musculus Raf1 gene Proteins 0.000 description 5
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 5
- 238000011374 additional therapy Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000003915 cell function Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 229960003301 nivolumab Drugs 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000009097 single-agent therapy Methods 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 4
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 4
- 241000282567 Macaca fascicularis Species 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 230000000139 costimulatory effect Effects 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 210000003162 effector t lymphocyte Anatomy 0.000 description 4
- 238000010228 ex vivo assay Methods 0.000 description 4
- 230000009036 growth inhibition Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 238000007913 intrathecal administration Methods 0.000 description 4
- UEPXBTCUIIGYCY-UHFFFAOYSA-N n-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-ylpyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide Chemical compound C1=C(C=2C=C(N=C(OCCO)C=2)N2CCOCC2)C(C)=CC=C1NC(=O)C1=CC=NC(C(F)(F)F)=C1 UEPXBTCUIIGYCY-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 102220197775 rs1057519695 Human genes 0.000 description 4
- 102200055464 rs113488022 Human genes 0.000 description 4
- 102200006539 rs121913529 Human genes 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- -1 troches Substances 0.000 description 4
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- 229940045513 CTLA4 antagonist Drugs 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 3
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 3
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 3
- 230000006052 T cell proliferation Effects 0.000 description 3
- 108091008874 T cell receptors Proteins 0.000 description 3
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 210000000612 antigen-presenting cell Anatomy 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229960002465 dabrafenib Drugs 0.000 description 3
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000002611 ovarian Effects 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000007420 reactivation Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 102200006657 rs104894228 Human genes 0.000 description 3
- 102200006532 rs112445441 Human genes 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 2
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 2
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 102000017578 LAG3 Human genes 0.000 description 2
- 101150030213 Lag3 gene Proteins 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 101500021084 Locusta migratoria 5 kDa peptide Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 2
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 229940124650 anti-cancer therapies Drugs 0.000 description 2
- 230000006023 anti-tumor response Effects 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 229950003054 binimetinib Drugs 0.000 description 2
- ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 238000002619 cancer immunotherapy Methods 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000037437 driver mutation Effects 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 229950001969 encorafenib Drugs 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 102000054751 human RUNX1T1 Human genes 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000003463 hyperproliferative effect Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N lgx818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 230000000803 paradoxical effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 210000003289 regulatory T cell Anatomy 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 102200006562 rs104894231 Human genes 0.000 description 2
- 102220014333 rs112445441 Human genes 0.000 description 2
- 102220117341 rs11554290 Human genes 0.000 description 2
- 102220197780 rs121434596 Human genes 0.000 description 2
- 102200006525 rs121913240 Human genes 0.000 description 2
- 102220197778 rs121913254 Human genes 0.000 description 2
- 102200055523 rs121913348 Human genes 0.000 description 2
- 102200006537 rs121913529 Human genes 0.000 description 2
- 102200006540 rs121913530 Human genes 0.000 description 2
- 102200006541 rs121913530 Human genes 0.000 description 2
- 102200007373 rs17851045 Human genes 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000011272 standard treatment Methods 0.000 description 2
- 238000012916 structural analysis Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229960004066 trametinib Drugs 0.000 description 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 2
- 238000011277 treatment modality Methods 0.000 description 2
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 229960003862 vemurafenib Drugs 0.000 description 2
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 241000754798 Calophyllum brasiliense Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101000867232 Escherichia coli Heat-stable enterotoxin II Proteins 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 101150061944 J2 gene Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- 206010027457 Metastases to liver Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710183263 Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101710150701 Serine/threonine-protein kinase C Proteins 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 208000012761 aggressive behavior Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940044684 anti-microtubule agent Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002257 antimetastatic agent Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 102000049555 human KRAS Human genes 0.000 description 1
- 229940126546 immune checkpoint molecule Drugs 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003259 immunoinhibitory effect Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 238000009099 neoadjuvant therapy Methods 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 231100001271 preclinical toxicology Toxicity 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000004223 radioprotective effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102220197820 rs121913227 Human genes 0.000 description 1
- 102200006533 rs121913535 Human genes 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940022511 therapeutic cancer vaccine Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000013298 xenograft nude mouse model Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/05—Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Biomedical Technology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662348720P | 2016-06-10 | 2016-06-10 | |
| US62/348,720 | 2016-06-10 | ||
| PCT/IB2017/053405 WO2017212442A1 (en) | 2016-06-10 | 2017-06-08 | Therapeutic uses of a c-raf inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2019517549A true JP2019517549A (ja) | 2019-06-24 |
| JP2019517549A5 JP2019517549A5 (pl) | 2020-07-16 |
Family
ID=59215827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018564296A Pending JP2019517549A (ja) | 2016-06-10 | 2017-06-08 | Ｃ−ｒａｆ阻害薬の治療的使用 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US20190175609A1 (pl) |
| EP (1) | EP3468595A1 (pl) |
| JP (1) | JP2019517549A (pl) |
| KR (1) | KR20190017767A (pl) |
| CN (1) | CN109310761A (pl) |
| AU (1) | AU2017279046B2 (pl) |
| BR (1) | BR112018075371A2 (pl) |
| CA (1) | CA3026876A1 (pl) |
| CL (1) | CL2018003530A1 (pl) |
| IL (1) | IL262961A (pl) |
| MX (1) | MX2018015353A (pl) |
| RU (1) | RU2018146886A (pl) |
| WO (1) | WO2017212442A1 (pl) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022550219A (ja) * | 2019-12-06 | 2022-11-30 | メッドシャイン ディスカバリー インコーポレイテッド | Ｐａｎ－ＲＡＦキナーゼ阻害剤としてのビアリール化合物 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109715163B (zh) * | 2016-09-19 | 2022-11-22 | 诺华股份有限公司 | 包含raf抑制剂和erk抑制剂的治疗组合 |
| JP7309614B2 (ja) | 2017-05-02 | 2023-07-18 | ノバルティス アーゲー | 組み合わせ療法 |
| US10945904B2 (en) | 2019-03-08 | 2021-03-16 | Auris Health, Inc. | Tilt mechanisms for medical systems and applications |
| CN113912591B (zh) * | 2020-07-08 | 2023-10-20 | 齐鲁制药有限公司 | 联芳基化合物 |
| CN117425650A (zh) * | 2021-06-04 | 2024-01-19 | 齐鲁制药有限公司 | 一种raf激酶抑制剂的晶型及其制备方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130252977A1 (en) * | 2012-03-07 | 2013-09-26 | Deciphera Pharmaceuticals, Llc | Raf Inhibitor Compounds |
| WO2014151616A1 (en) * | 2013-03-14 | 2014-09-25 | Novartis Ag | Biaryl amide compounds as kinase inhibitors |
| WO2015112800A1 (en) * | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-1 |
| WO2015112900A1 (en) * | 2014-01-24 | 2015-07-30 | Dana-Farber Cancer Institue, Inc. | Antibody molecules to pd-1 and uses thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE041469T2 (hu) * | 2014-02-04 | 2019-05-28 | Pfizer | PD-1 antagonista és VEGFR inhibitor kombinációja rák kezelésére |
| SG10202007111TA (en) * | 2014-07-15 | 2020-09-29 | Genentech Inc | Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors |
-
2017
- 2017-06-08 KR KR1020187035219A patent/KR20190017767A/ko not_active Application Discontinuation
- 2017-06-08 CN CN201780035192.1A patent/CN109310761A/zh active Pending
- 2017-06-08 US US16/307,920 patent/US20190175609A1/en not_active Abandoned
- 2017-06-08 MX MX2018015353A patent/MX2018015353A/es unknown
- 2017-06-08 WO PCT/IB2017/053405 patent/WO2017212442A1/en unknown
- 2017-06-08 BR BR112018075371-8A patent/BR112018075371A2/pt not_active Application Discontinuation
- 2017-06-08 EP EP17733028.9A patent/EP3468595A1/en not_active Withdrawn
- 2017-06-08 CA CA3026876A patent/CA3026876A1/en not_active Abandoned
- 2017-06-08 AU AU2017279046A patent/AU2017279046B2/en not_active Ceased
- 2017-06-08 RU RU2018146886A patent/RU2018146886A/ru not_active Application Discontinuation
- 2017-06-08 JP JP2018564296A patent/JP2019517549A/ja active Pending
-
2018
- 2018-11-12 IL IL262961A patent/IL262961A/en unknown
- 2018-12-07 CL CL2018003530A patent/CL2018003530A1/es unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130252977A1 (en) * | 2012-03-07 | 2013-09-26 | Deciphera Pharmaceuticals, Llc | Raf Inhibitor Compounds |
| WO2014151616A1 (en) * | 2013-03-14 | 2014-09-25 | Novartis Ag | Biaryl amide compounds as kinase inhibitors |
| WO2015112800A1 (en) * | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-1 |
| WO2015112900A1 (en) * | 2014-01-24 | 2015-07-30 | Dana-Farber Cancer Institue, Inc. | Antibody molecules to pd-1 and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| NAT. REV. DRUG DISCOV., 2014, VOL.13, NO.11, PP.828-851, JPN6021020965, ISSN: 0004925256 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022550219A (ja) * | 2019-12-06 | 2022-11-30 | メッドシャイン ディスカバリー インコーポレイテッド | Ｐａｎ－ＲＡＦキナーゼ阻害剤としてのビアリール化合物 |
| JP7214925B2 (ja) | 2019-12-06 | 2023-01-30 | メッドシャイン ディスカバリー インコーポレイテッド | Ｐａｎ－ＲＡＦキナーゼ阻害剤としてのビアリール化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2018015353A (es) | 2019-09-09 |
| US20190175609A1 (en) | 2019-06-13 |
| AU2017279046B2 (en) | 2020-07-02 |
| WO2017212442A1 (en) | 2017-12-14 |
| CL2018003530A1 (es) | 2019-02-15 |
| BR112018075371A2 (pt) | 2019-03-19 |
| KR20190017767A (ko) | 2019-02-20 |
| AU2017279046A1 (en) | 2018-12-06 |
| CA3026876A1 (en) | 2017-12-14 |
| IL262961A (en) | 2018-12-31 |
| EP3468595A1 (en) | 2019-04-17 |
| RU2018146886A (ru) | 2020-07-10 |
| CN109310761A (zh) | 2019-02-05 |
| RU2018146886A3 (pl) | 2020-10-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108025051B (zh) | 包含抗pd-1抗体分子的联合疗法 | |
| US20180177872A1 (en) | Combination of PD-1 antagonist with an EGFR inhibitor | |
| JP2019517549A (ja) | Ｃ−ｒａｆ阻害薬の治療的使用 | |
| JP2019516712A (ja) | 癌を処置するためのグルタミン酸調節剤と免疫療法の併用 | |
| KR20180088907A (ko) | Pd-1에 대한 항체 분자 및 그의 용도 | |
| TWI795347B (zh) | 使用抗ｐｄ-１抗體與抗ｃｔｌａ-４抗體之組合以治療肺癌 | |
| JP2024012300A (ja) | 医薬併用 | |
| CN111973739B (zh) | 抗pd-l1单克隆抗体治疗癌症的用途 | |
| JP2022547550A (ja) | Ｐｄ－１軸阻害剤及び抗ペリオスチン抗体の使用により癌を処置する方法。 | |
| TW202417479A (zh) | 用於治療癌症之抗-pd-1活性劑、抗-tim-3活性劑及抗-lag-3活性劑之組合療法 | |
| KR20190107719A (ko) | 세리티닙 및 항-pd-1 항체 분자의 조합물에 대한 투여 일정 | |
| CN116568305A (zh) | 用于治疗肺癌的方法以及包含krasg12c抑制剂和pd-l1结合拮抗剂的组合物 | |
| JP2023504630A (ja) | 腫瘍治療のための二重特異性融合タンパク質 | |
| US20240317874A1 (en) | Anti-ox40 monoclonal antibody and methods of use thereof | |
| RU2788092C2 (ru) | Молекулы антител к pd-1 и их применения | |
| WO2020044252A1 (en) | Dosage regimes for anti-m-csf antibodies and uses thereof | |
| JP2019218346A (ja) | がんの処置に使用するための５−ブロモ−２，６−ジ−（１ｈ−ピラゾール−１−イル）ピリミジン−４−アミン |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200605 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200605 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210601 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210831 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211201 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220426 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20221122 |